Background: The diagnosis of cutaneous adversities in the cancer patient is especially difficult, given the complexity of their illness and combination protocols used for the treatment. The present study was undertaken to know the spectrum of cutaneous adversities in patients undergoing chemotherapy and the drug(s) most commonly associated with it. Materials and Methods: A total of 1000 patients with malignancies under chemotherapy in the oncology ward and outpatient department were screened in this observational study from January 2013 to February 2015. Relevant investigations for diagnosis of malignancies under chemotherapy and dermatological disorders were carried out. Results: Three hundred and eighty-four patients presented with cutaneous adversities of chemotherapy. The most common was anagen effluvium (78.6%), followed by xerosis (4.4%), thrombophlebitis (3.1%), generalised pruritus (2.9%), melanonychia (2.9%), hand-foot syndrome (2.6%), extravasation reactions (1.8%), flagellate dermatosis (1.3%), prurigo nodularis (0.8%), exfoliation (0.5%), ichthyosis (0.5%), papulopustular rash (0.3%), bullous photodermatitis (0.3%), and Sweet's syndrome (0.3%). Chemotherapeutic drugs were mostly given in combinations. Most common drugs to cause anagen effluvium were alkylating agents in combinations, hand-foot syndrome by taxanes (docetaxel), flagellate dermatoses by antitumour antibiotics (bleomycin), and exfoliation by antimetabolites (methotrexate). The limitation of this study was to imply a specific drug as the causation of the cutaneous adversities since the chemotherapy mostly consisted of combination protocols. Therefore, we have tried to associate the drug combination itself. Conclusion: Chemotherapeutic drugs produce a range of cutaneous adversities, certain specific adversities pertaining to drugs, and their combinations have been implicated which should be looked for and managed accordingly. Knowledge of the adverse effects of anticancer drugs will help reduce the psychological trauma and improve the quality of life.

What was known?
In earlier studies, small sample sizes were taken and cutaneous adverse drug reactions of single cancer chemotherapy drugs were known.

Introduction

New chemotherapeutic agents have been used for the treatment of cancer.[1] This increased use has led to rise in the incidence of cutaneous side effects and worsening of the quality of life. The most common cutaneous adverse manifestations are anagen effluvium, hyperpigmentation, hand-foot syndrome, radiation recall, hypersensitivity, extravasation injuries, and nail dystrophies. They are rarely fatal but may result in significant morbidity, cosmetic disfigurement, and psychological distress.[2] The aim of our study is to find the spectrum of cutaneous adversities and frequency of association with the chemotherapeutic agent(s).

Materials and Methods

An observational study was conducted at our centre, after obtaining ethical committee clearance. All cancer patients starting from January 2013 to February 2015 were screened. After excluding patients on concurrent radiotherapy, cutaneous adversities due to internal malignancies, and who already had cutaneous symptoms before the initiation of chemotherapy, 1000 consecutive cancer patients, who received chemotherapy in the oncology department, were included in the study.

In all patients, epidemiological data, malignancy, dermatological complaints, cutaneous and systemic examination, and chemotherapy treatment details were recorded. Cutaneous lesions were diagnosed on the basis of typical clinical manifestations. Skin biopsies for histopathology were done in relevant cases.

Results

Out of 1000 cancer patients studied, 295 (29.5%) were male and 705 (70.5%) were female. The mean age was 46.8 ± 16.1 years (range: 4–80 years). They had 67 different types of malignancies, out of which the most common was genitourinary malignancy in 241 (24.1%) patients, followed by breast carcinoma in 147 (14.7%) patients. There were 384 patients who presented with 14 different types of dermatological manifestations [Table 1], out of which anagen effluvium was most common, found in 302 (78.6%) patients. The various cutaneous adversities of chemotherapeutic agent(s) and their frequency distribution are depicted in [Table 2].

Chemotherapeutic agents individually or in combination have cutaneous side effects that worsen patient's quality of life. Appropriate management is, therefore, necessary to improve the quality of life and to better the clinical outcome.

In our study, among the patients who presented with dermatological side effects, anagen effluvium was the most common lesion found in 302 (78.6%) patients followed by xerosis in 17 (4.4%), thrombophlebitis in 12 (3.1%), and melanonychia and generalised pruritus in 11 (2.9%) patients each [Table 1]. Mucositis is a known common adversity, but surprisingly, in our observation, none of the patients had it. This might be due to the proper care taken by the patients.

Trueb RM observed that chemotherapy-induced hair loss [Figure 1] occurred with an estimated incidence of 65%.[3] It occurs in >80% of patients treated with antimicrotubule agents; 60 to 100% with topoisomerase inhibitors; >60% with alkylating agents and 10 to 50% with antimetabolite which was similar to a study by Hussein.[4] In our study, the incidence is 30.2% among all patients on chemotherapy. We found that anagen effluvium was seen in all of the patients receiving adriamycin + dacarbazine, carboplatin + docetaxel, paclitaxel + mitomycin + 5-fluorouracil (5-FU) followed by 84.7% of patients receiving ifosfamide + etoposide and 78% of patients receiving oxaliplatin + cyclophosphamide + adriamycin. Hair loss was seen in 85 (8.5%) patients after 1st cycle and in 88 (8.8%) patients after the 2nd cycle.

Each of the major classes of antineoplastic agents (alkylating agents, antimetabolites, antibiotics, plant alkaloids, nitrosoureas, and enzymes) includes drugs capable of producing cutaneous reactions including pruritus. Patients receiving antineoplastic drugs frequently report dry skin and scaling thought to be related to effects on sebaceous and sweat glands.[9] In our study, generalised pruritus was seen in 11 (2.9%) patients on chemotherapy. It was seen in 55.5% of patients on 5-FU + cyclophosphamide + epirubicin therapy and in 4.2% having cisplatin + 5-FU therapy. Prurigo nodularis was found in 3 (2.5%) patients receiving paclitaxel + carboplatin therapy.

Ziemer et al[10] observed that flagellate dermatitis [Figure 5] and subsequent hyperpigmentation in the skin were fairly common among patients receiving bleomycin, with reported incidence between 8% and 22% whereas Júlio César Gomes Silveira et al[11] observed its occurrence was variable, as it was described in a percent range from 8% to 66% of cases in different studies. In our study, it was seen in 5 cases. Two patients with bleomycin and 1 patient with paclitaxel + carboplatin + bleomycin therapy showed flagellate dermatosis.

Papulopustular rash was reported with gefitinib, cetuximab, and ABVD regimen.[5] We observed it in a case with 5-FU + oxaliplatin therapy.

Phlebitis is an inflammatory response to intravenously injected chemotherapy drugs that may last for weeks or months and leads to various types of vein damage including pain, erythema and swelling, and thickening of injection area and finally, fever.[13] Thrombophlebitis was seen in 12 patients treated with cytarabine + daunorubicin, carboplatin + 5-FU, and 5-FU + oxaliplatin in our study. Chemotherapy-induced phlebitis incidence has been reported as 70%; it increases the probability of embolism affecting the health of the patients.[14]

It has been reported that Sweet's syndrome developed secondary to administration of imatinib mesylate for the treatment of chronic myeloid leukaemia.[15] In our study also one patient who received imatinib, developed Sweet's syndrome.

In our study, we found cisplatin + paclitaxel caused cutaneous side effects as anagen effluvium in 55.55% and melanonychia in 7.58% of the patients. The main side effects of this combination regimen were myelosuppression, gastrointestinal reactions, and peripheral neuropathy in a study by Zhao et al.[16]

In 141 patients who received Cisplatin + 5-FU regimen cutaneous adversities seen were anagen effluvium in 7.8%, xerosis in 4.96%, generalised pruritus in 4.25%, and extravasation reactions in 3.54%. This is similar to a study by the Christie NHS Foundation Trust.[17]

Similarly, therapy with paclitaxel + carboplatin led to anagen effluvium in 33.33% and prurigo nodularis in 2.5% of 120 patients. A diffuse rash had been reported after the administration of this combination therapy.[18]

The limitation of this study was the inability of pinpointing a single drug responsible for a particular dermatological adversary since the chemotherapy mostly constituted of combination protocol. Therefore, we have tried to associate the drug combination itself.

Conclusion

We conclude that 78.6% of the patients having dermatological adversities presented with anagen effluvium most commonly by alkylating agents, cytotoxic agents, and taxanes in various combinations. Similarly, bleomycin was found to be the most probable cause of flagellate dermatoses in combinations. Alkylating agents and antimetabolites were most frequently implicated in xerosis, thrombophlebitis, generalised pruritus, extravasation reactions, and papulopustular rash. Hand-foot syndrome was associated most commonly with taxanes followed by epidermal growth factor receptor antagonist (sunitinib) and antimetabolites. Melanonychia, bullous photodermatitis, and prurigo nodularis were seen mostly by alkylating agents and their various combinations. Similarly, exfoliation and ichthyosis were caused by methotrexate while Sweet's syndrome by tyrosine kinase inhibitor imatinib.

These reactions occur in varying degrees of frequency and severity within each class of chemotherapeutic drugs which may result in significant morbidity, obliging physicians to suspend therapy. Proper treatment may allow achievement of ideal durations of chemotherapy administration, as well as the optimization of response rates. It is stressed that counseling of the patients and their attendants before initiation of chemotherapy may reduce the psychological trauma of the cosmetically unacceptable adversities and hence improvise the lifestyle management. Cooperation between oncologist and dermatologist is also fundamental to make the best decision for the patients and to implement preventive measures.

What is new?
Here, we have taken a large sample of 1000 cancer patients under chemotherapy having cutaneous adversities in 394 patients and studied not only about the cutaneous adverse drug reactions of the various combination protocols and single cancer chemotherapy drugs but also their frequency of association.